EP0252286A2 - Pharmaceutical preparations for topical use, process for their manufacture and their use - Google Patents
Pharmaceutical preparations for topical use, process for their manufacture and their use Download PDFInfo
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- EP0252286A2 EP0252286A2 EP87107958A EP87107958A EP0252286A2 EP 0252286 A2 EP0252286 A2 EP 0252286A2 EP 87107958 A EP87107958 A EP 87107958A EP 87107958 A EP87107958 A EP 87107958A EP 0252286 A2 EP0252286 A2 EP 0252286A2
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- active ingredient
- pharmaceutical preparation
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- topical
- water
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- 0 CCC1C*CC1 Chemical compound CCC1C*CC1 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the invention relates to new pharmaceutical preparations for topical, that is to say dermal, application which as an active ingredient is a compound of the formula I.
- 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino] ethyl] formanilide (formoterol), or one of their pharmaceutically usable salts, in particular their semifumarate contain, processes for the preparation of such pharmaceutical preparations and the use of compounds of the formula I and their pharmaceutically usable salts.
- Pharmaceutically usable salts of a compound of formula I are pharmaceutically usable acid addition salts, for example salts with inorganic acids, such as mineral acids, with sulfamic acids, such as cyclohexylsulfamic acid, with organic carboxylic acids, such as lower alkane carboxylic acids or optionally unsaturated dicarboxylic acids, with aliphatic or hydroxy-substituted or oxo-substituted or with aliphatic carboxylic acids with aliphatic or aromatic sulfonic acids, for example sulfates or hydrohalides, such as hydrobromides or hydrochlorides, oxalates, malonates, fumarates or maleinates, tartrates, pyruvates or citronates, and sulfonates, such as methane, benzene or p-toluenesulfonates.
- Lower alkane carboxylic acids are preferably to be understood as those which contain up
- the pharmaceutically usable salts of a compound of the formula I can also be in the form of their hydrates or include other pharmaceutically acceptable solvents used, for example, for crystallization.
- a free compound or its salts are to be understood above and below as appropriate and expediently also the corresponding salts or the free compound. Accordingly, below formoterol means both the free base and its pharmaceutically usable salts, in particular its semifumarate.
- Formoterol and its pharmaceutically usable salts are known and are described, for example, in German Offenlegungsschrift DE-2 305 092 (Yamanouchi Pharmaceutical Co. Ltd., Tokyo).
- formoterol and its pharmaceutically usable salts belong to the class of the ⁇ -adrenergic stimulators and, due to their great activity on the smooth respiratory muscles, are stated to be suitable as bronchodilator agents, oral and parenteral dosage forms being described.
- formoterol in particular is an additional valuable pharmacological property in the case of topical, i.e. dermal, application to the skin and / or mucous membrane a strong anti-inflammatory (dermatological), i.e. topical anti-inflammatory, has effect.
- compositions for topical i.e. dermal
- application to the skin and / or mucous membrane to understand dermatological pharmaceutical preparations for external use on the outer skin, including the conjunctiva, the lips and the genital and anal region.
- formoterol and its pharmaceutically usable salts can be demonstrated in suitable animal models.
- Studies with formoterol in the form of the free base in the concentration range from approximately 0.03 to approximately 30 mg / ml on the experimental ear edema of the rat induced by croton oil resulted in an inhibitory concentration EC50 of approximately 0.5 mg / ml and in the concentration range of approximately 0.01 up to about 10 mg / ml on the experimental ear edema of the mouse induced by croton oil, an inhibitory concentration EC50 of about 0.32 mg / ml [methodology: based on G. Tonelli et al., Endocrinology 77 , 625 (1965)].
- Formoterol is therefore particularly suitable as a dermatological anti-inflammatory agent for the treatment of inflammatory or proliferative dermatoses associated with inflammation, in particular in the form of the topically applicable dermatological application according to the invention pharmaceutical preparations. It can be used in a wide variety of inflammatory dermatoses, in particular those of an acute and subchronic type, both allergic and non-allergic in nature.
- Formoterol is also suitable for the treatment of proliferative skin diseases, in particular those associated with inflammation, such as psoriasis, and can also be used for the treatment of skin irritations, rashes and burns as well as for the treatment of inflammation of the conjunctiva, the lips and the genital and Find anal region use.
- the present invention also relates to a method for the treatment of inflammatory skin diseases of the type described above, characterized by the topical, i.e. dermal application of a compound of formula I or one of its pharmaceutically acceptable salts.
- the invention also relates to the use of a compound of the formula I or one of its pharmaceutically usable salts for the treatment of inflammatory skin diseases of the most varied of origins, in particular for the treatment of dermatoses of the type described above, and for the production of the dermatological pharmaceutical preparations according to the invention.
- compositions according to the invention which contain a compound of the formula I, in particular formoterol, or pharmaceutically acceptable salts thereof, are those for dermatological use on warm-blooded animals, the pharmacological active ingredient being contained alone or together with a pharmaceutically acceptable carrier material.
- the daily dosage of the active ingredient depends on the age and individual condition as well as on the mode of administration.
- Corresponding agents with an active ingredient content of about 0.00001 to about 1 percent by weight, for example in the form of creams, ointments or solutions, can be applied, for example, 2 to 3 times a day.
- Suitable dermatologically applicable pharmaceutical preparations are primarily creams, ointments, fatty ointments, pastes, gels, foams, tinctures and solutions, and for treating the conjunctiva, eye drops, each of for example from about 0.00001 to about 1 percent by weight, in particular from about 0 , 0005 to about 0.5 percent by weight of the active ingredient.
- Creams are oil-in-water emulsions that contain more than 50% water.
- Fatty alcohols e.g. Lauryl, cetyl or stearyl alcohol, fatty acids e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil.
- Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g.
- Fatty acid esters of polyalcohols or ethylene oxide adducts thereof such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are commonly used in the presence of fatty alcohols, e.g. Cetyl alcohol or stearyl alcohol.
- Additions to the water phase include Agents which reduce the drying out of the cream, e.g. Polyalcohols, such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
- Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases.
- the fatty phase primarily includes hydrocarbons, for example petroleum jelly, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols or wool wax, in order to improve their water binding capacity.
- Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), for example sorbitan oleate and / or sorbitan iso stearate.
- Additives to the water phase include humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and / or polyethylene glycol, and also preservatives, fragrances, etc.
- Fatty ointments are anhydrous and contain hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fats, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate, as well as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments which increase the water absorption capacity.
- hydrocarbons e.g. Paraffin, petroleum jelly and / or liquid paraffins
- natural or partially synthetic fats e.g.
- coconut fatty acid triglyceride or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate,
- Pastes are creams and ointments with secretion-absorbing powder components such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
- metal oxides e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
- aqueous and water-free or low-water gels consist of swellable, gel-forming materials.
- Transparent hydrogels based on inorganic or organic macromolecules are primarily used.
- High-molecular inorganic components with gel-forming properties are predominantly water-containing silicates, such as aluminum silicates, for example concrete, magnesium-aluminum silicates, for example Veegum, or colloidal silica, for example Aerosil.
- Natural, semisynthetic or synthetic macromolecules, for example, are used as high-molecular organic substances.
- Natural and semi-synthetic polymers are derived, for example, from polysaccharides with a wide variety of carbohydrate components, such as celluloses, starches, tragacanth, arabic gum, agar-agar, gelatin, alginic acid and their salts, for example sodium alginate, and their derivatives, such as lower alkyl celluloses, for example methyl or Ethyl celluloses, carboxy or hydroxy lower alkyl cellulose, for example carboxymethyl or hydroxyethyl celluloses.
- the building blocks of synthetic, gel-forming macromolecules are, for example appropriately substituted unsaturated aliphatics such as vinyl alcohol, vinyl pyrrolidine, acrylic or methacrylic acid.
- polymers examples include polyvinyl alcohol derivatives, such as polyviol, polyvinylpyrrolidines, such as Kollidon, polyacrylates or polymethacrylates, such as Rohagit S or Eudispert.
- Common additives such as preservatives or fragrances, can be added to the gels.
- Foams are e.g. administered from pressure vessels and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro lower alkanes e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents.
- the oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes.
- the emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual additives such as preservatives, etc.
- Tinctures and solutions mostly have a watery-ethanol base, which among other things Polyalcohols, e.g. Glycerin, glycols and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances such as fatty acid esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added.
- Polyalcohols e.g. Glycerin, glycols and / or polyethylene glycol, as humectants to reduce evaporation
- refatting substances such as fatty acid esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added.
- Eye drops are mostly sterile aqueous solutions that are adjusted to the physiological pH range from 6 to 8.
- concentration of the buffers used for pH adjustment such as phosphate or acetate buffers, is selected so that the pH of the tear fluid is not influenced over the long term and a pain sensation is triggered.
- the isotony with the Lacrimal fluid is usually achieved by adding salts, such as sodium citrate or preferably sodium chloride, or mannitol.
- auxiliaries for example antioxidants such as sodium pyrosulfite, preservatives such as benzalkonium chloride, cetylpyridinium chloride or 2-phenylethyl alcohol, and optionally solubilizers, for example polyoxyethylene sorbitan monooleate, polyoxyethylene glycol or ⁇ - or ⁇ -cyclodextrin, are added.
- antioxidants such as sodium pyrosulfite
- preservatives such as benzalkonium chloride, cetylpyridinium chloride or 2-phenylethyl alcohol
- solubilizers for example polyoxyethylene sorbitan monooleate, polyoxyethylene glycol or ⁇ - or ⁇ -cyclodextrin
- the dermatologically applicable pharmaceutical preparations are produced in a manner known per se by mixing with conventional pharmaceutical auxiliaries, e.g. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary.
- conventional pharmaceutical auxiliaries e.g. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary.
- the active ingredient is usually dissolved in the latter before the emulsification; to produce suspensions in which the active ingredient is suspended in the emulsion, the active ingredient is mixed with part of the base after the emulsification and then added to the rest of the formulation.
- Example 1 An ointment containing 0.05% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] -formanilide or its semifumarate, can be prepared as follows: Composition: Active substance 0.05% Vaseline 45.00% Paraffin oil 19.60% Cetyl alcohol 5.00% Beeswax 5.00% Sorbitan sesquioleate 5.00% p-hydroxybenzoic acid ester 0.20% Water, demineralized, up to 100.00%
- the fatty substances and emulsifiers are melted together.
- the preservative is dissolved in water and the solution is emulsified into the fat melt at elevated temperature. After cooling, a suspension of the active ingredient is incorporated into part of the fat melt in the emulsion.
- Example 2 A cream containing 0.5% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] -formanilide or its semifumarate, can be prepared as follows: Composition: Active ingredient 0.5% Isopropyl palmitate 8.0% Cetyl palmitate 1.5% Silicone oil 100 0.5% Sorbitan monostearate 3.0% Polysorbate 60 3.5% 1,2-propylene glycol PH 20.0% Acrylic acid polymer 0.5% Triethanolamine 0.7% Water, demineralized, up to 100.0%
- the acrylic acid polymer is suspended in a mixture of demineralized water and 1,2-propylene glycol. Triethanolamine is then added with stirring, giving a mucus.
- a mixture of isopropyl palmitate, cetyl palmitate, silicone oil, Sorbitan monostearate and polysorbate are heated to about 75 ° and incorporated into the mucus, which has also been heated to about 75 °, with stirring.
- the cream base cooled to room temperature is then used to produce a concentrate with the active ingredient.
- the concentrate is homogenized by means of a continuous homogenizer and then added to the base in portions.
- Example 3 A cream containing 0.05% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino -ethyl] -formanilide or its semifumarate can be obtained as follows: Composition: Active substance 0.05% Cetyl palmitate PH 2.00% Cetyl alcohol PH 2.00% Triglyceride mixture of saturated medium fatty acids 5.00% Stearic acid 3.00% Glycerol stearate pH 4.00% Cetomacrogol 1000 1.00% microcrystalline cellulose 0.50% 1,2-propylene glycol, dist. 20.00% Water, demineralized, up to 100.00%
- Cetyl alcohol, cetyl palmitate, the triglyceride mixture, stearic acid and glycerol stearate are melted together.
- the microcrystalline cellulose is dispersed in part of the water.
- Cetomacrogol is dissolved in the remaining part of the water and the propylene glycol and the mucus are mixed with it.
- the fat phase is then added to the water phase with stirring and stirred cold.
- the active ingredient is rubbed with part of the base and the rubbing is then incorporated into the rest of the cream.
- Example 4 A transparent hydrogel containing 0.5% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] -formanilide or its semi-fumarate is made as follows: Composition: Active ingredient 0.5% Propylene glycol 10.0 - 20.0% Isopropanol 20.0% Hydroxypropyl methyl cellulose 2.0% Water ad 100.0%
- the hydroxypropyl methyl cellulose is swollen in the water.
- the active ingredient is dissolved in a mixture of isopropanol and propylene glycol.
- the active ingredient solution is then mixed with a swollen cellulose derivative and, if desired, fragrances (0.1%) are added.
- Example 5 A transparent hydrogel containing 0.005% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino] -ethyl] -formanilide or its semi-fumarate is made as follows: Composition: Active ingredient 0.005% Propylene glycol 20.0% Isopropanol 20.0% Acrylic acid polymer 2.0% Triethanolamine 3.0% Water ad 100.0%
- Acrylic acid polymer and water are dispersed and neutralized with triethanolamine.
- the active ingredient is dissolved in a mixture of isopropanol and propylene glycol.
- the active ingredient solution is then mixed with the gel, it being possible, if desired, to add fragrance (0.1%).
- Example 6 A foam spray containing 0.01% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] - formanilide or its semifumarate, can be prepared as follows: Composition: Active ingredient 0.01% Cetyl alcohol PH 1.70% Paraffin oil, viscous 1.00% Isopropyl myristate 2.00% Cetomacrogol 1000 2.40% Sorbitan monostearate 1.50% 1,2-propylene glycol pH 5.00% Methyl paraben 0.18% Propylparaben 0.02% Chemoderm 314 0.10% Water, demineralized, up to 100.00%
- Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan stearate are melted together. Methyl and propyl paraben are dissolved in hot water. The melt and the solution are then mixed. The active ingredient, suspended in propylene glycol, is incorporated into the base. Chemoderm is then added and water is added to the final weight.
- Example 7 Eye drops containing 0.3% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino] -ethyl] -formanilide or its semi-fumarate, can be prepared for example as follows: Composition (for 10,000 bottles with 10 ml eye drop solution): Active ingredient 0.30% Disodium phosphate 0.31% Citric acid 0.15% Sodium chloride 0.35% Sodium pyrosulfite 0.10% Benzalkonium chloride 0.01% Water, demineralized, up to 100.00%
- the active ingredient and all of the additives mentioned are stirred into 80 l of demineralized water under a nitrogen atmosphere. After all components have completely dissolved, the solution is made up to 100 l with demineralized water, sterilized in an autoclave at 120 ° for 20 minutes and then filtered under sterile conditions through a membrane filter (pore diameter: 0.2 ⁇ m). Each 10 ml of the filtrate is filled into a bottle with a dropper cap under aseptic conditions.
- Example 8 In a manner analogous to that described in Examples 1 to 7, it is also possible to prepare dermatologically applicable pharmaceutical preparations which contain another pharmaceutically acceptable salt of formoterol.
- Example 9 Dermatologically applicable pharmaceutical preparations which contain another compound of the formula I or a pharmaceutically acceptable salt thereof can also be prepared in a manner analogous to that described in Examples 1 to 7.
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Abstract
Pharmazeutische Präparate zur topischen, d.h. dermalen, Applikation, die als Wirkstoff eine Verbindung der Formel I <IMAGE> insbesondere 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino]-äthyl]-formanilid (Formoterol), oder eines ihrer pharmazeutisch verwendbaren Salze, insbesondere ihr Semifumarat, enthalten, werden zur Behandlung entzündlicher Hauterkrankungen vorgeschlagen.Pharmaceutical preparations for topical, i.e. dermal application, the active ingredient being a compound of the formula I <IMAGE>, in particular 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2 -yl] -amino] -ethyl] -formanilide (formoterol), or one of its pharmaceutically acceptable salts, especially its semifumarate, are proposed for the treatment of inflammatory skin diseases.
Description
Die Erfindung betrifft neue pharmazeutische Präparate zur topischen, d.h. dermalen, Applikation, die als Wirkstoff eine Verbindung der Formel I
Pharmazeutisch verwendbare Salze einer Verbindung der Formel I sind pharmazeutisch verwendbare Säureadditionssalze, beispielsweise Salze mit anorganischen Säuren, wie Mineralsäuren, mit Sulfaminsäuren, wie Cyclohexylsulfaminsäure, mit organischen Carbonsäuren, wie Niederalkancarbonsäuren oder gegebenenfalls ungesättigten Dicarbonsäuren, mit durch Hydroxy und/oder Oxo substituierten aliphatischen Carbonsäuren oder mit aliphatischen oder aromatischen Sulfonsäuren, beispielsweise Sulfate oder Hydrohalogenide, wie Hydrobromide oder Hydrochloride, Oxalate, Malonate, Fumarate oder Maleinate, Tartrate, Pyruvate oder Citronate sowie Sulfonate, wie Methan-, Benzol- oder p-Toluolsulfonate. Dabei sind unter Niederalkancarbonsäuren vorzugsweise solche zu verstehen, die im Niederalkylteil bis und mit 7, vor allem bis und mit 4 Kohlenstoffatome (C-Atome) enthalten.Pharmaceutically usable salts of a compound of formula I are pharmaceutically usable acid addition salts, for example salts with inorganic acids, such as mineral acids, with sulfamic acids, such as cyclohexylsulfamic acid, with organic carboxylic acids, such as lower alkane carboxylic acids or optionally unsaturated dicarboxylic acids, with aliphatic or hydroxy-substituted or oxo-substituted or with aliphatic carboxylic acids with aliphatic or aromatic sulfonic acids, for example sulfates or hydrohalides, such as hydrobromides or hydrochlorides, oxalates, malonates, fumarates or maleinates, tartrates, pyruvates or citronates, and sulfonates, such as methane, benzene or p-toluenesulfonates. Lower alkane carboxylic acids are preferably to be understood as those which contain up to and including 7, especially up to and with 4, carbon atoms (C atoms) in the lower alkyl part.
Die pharmazeutisch verwendbaren Salze einer Verbindung der Formel I können auch in der Form ihrer Hydrate vorliegen oder andere, beispielsweise zur Kristallisation verwendete, pharmazeutisch unbedenkliche Lösungsmittel einschliessen.The pharmaceutically usable salts of a compound of the formula I can also be in the form of their hydrates or include other pharmaceutically acceptable solvents used, for example, for crystallization.
Infolge der engen Beziehung zwischen einer Verbindung der Formel I in freier Form und in Form ihrer pharmazeutisch verwendbaren Salze sind vorstehend und nachfolgend unter einer freien Verbindung oder ihren Salzen sinn- und zweckgemäss gegebenenfalls auch die entsprechenden Salze bzw. die freie Verbindung zu verstehen. Nachstehend sind dementsprechend unter Formoterol sowohl die freie Base als auch seine pharmazeutisch verwendbaren Salze, insbesondere sein Semifumarat, zu verstehen.As a result of the close relationship between a compound of the formula I in free form and in the form of its pharmaceutically usable salts, a free compound or its salts are to be understood above and below as appropriate and expediently also the corresponding salts or the free compound. Accordingly, below formoterol means both the free base and its pharmaceutically usable salts, in particular its semifumarate.
Formoterol und seine pharmazeutisch verwendbaren Salze sind bekannt und beispielsweise in der deutschen Offenlegungsschrift DE-2 305 092 (Yamanouchi Pharmaceutical Co. Ltd., Tokio) beschrieben.Formoterol and its pharmaceutically usable salts are known and are described, for example, in German Offenlegungsschrift DE-2 305 092 (Yamanouchi Pharmaceutical Co. Ltd., Tokyo).
Wie dort dargelegt, gehören Formoterol und seine pharmazeutisch verwendbaren Salze zur Klasse der β-adrenergen Stimulatoren und sind angabegemäss aufgrund ihrer grossen Aktivität auf die glatte Atmungsmuskulatur als bronchodilatatorische Mittel geeignet, wobei orale und parenterale Darreichungsformen beschrieben werden.As stated there, formoterol and its pharmaceutically usable salts belong to the class of the β-adrenergic stimulators and, due to their great activity on the smooth respiratory muscles, are stated to be suitable as bronchodilator agents, oral and parenteral dosage forms being described.
Pharmazeutische Präparate von Verbindungen der Formel I beziehungsweise ihren pharmazeutisch verwendbaren Salzen zur topischen, d.h. dermalen, Applikation auf die Haut und/oder Schleimhaut sind dagegen neu. Im Stand der Technik finden sich keinerlei diesbezügliche Hinweise.In contrast, pharmaceutical preparations of compounds of the formula I or their pharmaceutically usable salts for topical, ie dermal, application to the skin and / or mucous membrane are new. In the state of the art there are no references in this regard.
Im Rahmen der vorliegenden Erfindung zeigte sich nun überraschenderweise, dass insbesondere Formoterol als zusätzliche wertvolle pharmakologische Eigenschaft bei topischer, d.h. dermaler, Applikation auf die Haut und/oder Schleimhaut eine stark ausgeprägte antiphlogistische (hautphlogistatische), d.h. topisch-antiinflammatorische, Wirkung aufweist.In the context of the present invention, it has now surprisingly been found that formoterol in particular is an additional valuable pharmacological property in the case of topical, i.e. dermal, application to the skin and / or mucous membrane a strong anti-inflammatory (dermatological), i.e. topical anti-inflammatory, has effect.
Vorstehend und nachfolgend sind unter pharmazeutischen Präparaten zur topischen, d.h. dermalen, Applikation auf die Haut und/oder Schleimhaut dermatologische pharmazeutische Präparate zur äusserlichen Anwendung auf der äusseren Haut, einschliesslich der Augenbindehaut, der Lippen und der Genital- und Analregion, zu verstehen.Above and below, pharmaceutical preparations for topical, i.e. dermal, application to the skin and / or mucous membrane to understand dermatological pharmaceutical preparations for external use on the outer skin, including the conjunctiva, the lips and the genital and anal region.
Die antiphlogistische Wirkung von Formoterol und seinen pharmazeutisch verwendbaren Salzen lässt sich an geeigneten Tiermodellen zeigen. So ergaben Untersuchungen mit Formoterol in Form der freien Base im Konzentrationsbereich von etwa 0,03 bis etwa 30 mg/ml am durch Crotonöl induzierten experimentellen Ohroedem der Ratte eine Hemmkonzentration EC₅₀ von etwa 0,5 mg/ml und im Konzentrationsbereich von etwa 0,01 bis etwa 10 mg/ml am durch Crotonöl induzierten experimentellen Ohroedem der Maus eine Hemmkonzentration EC₅₀ von etwa 0,32 mg/ml [Methodik: in Anlehnung an G. Tonelli et al., Endocrinology 77, 625 (1965)].The antiphlogistic effect of formoterol and its pharmaceutically usable salts can be demonstrated in suitable animal models. Studies with formoterol in the form of the free base in the concentration range from approximately 0.03 to approximately 30 mg / ml on the experimental ear edema of the rat induced by croton oil resulted in an inhibitory concentration EC₅₀ of approximately 0.5 mg / ml and in the concentration range of approximately 0.01 up to about 10 mg / ml on the experimental ear edema of the mouse induced by croton oil, an inhibitory concentration EC₅₀ of about 0.32 mg / ml [methodology: based on G. Tonelli et al., Endocrinology 77 , 625 (1965)].
Eine stark ausgeprägte antiphlogistische Wirkung lässt sich auch am durch Arachidonsäure induzierten experimentellen Ohroedem der Maus nachweisen. In diesem Modell ergab sich für Formoterol in Form der freien Base im Konzentrationsbereich von etwa 0,0005 bis etwa 50 mg/ml eine Hemmkonzentration EC₅₀ von etwa 0,0026 mg/ml [Methodik: in Anlehnung an J.M. Young et al, J.Invest.Dermatol.82, 367 (1984)].A strong anti-inflammatory effect can also be demonstrated in the experimental ear edema of the mouse induced by arachidonic acid. In this model, an inhibitory concentration EC₅₀ of approximately 0.0026 mg / ml was found for formoterol in the form of the free base in the concentration range from approximately 0.0005 to approximately 50 mg / ml [methodology: based on JM Young et al, J.Invest .Dermatol. 82 , 367 (1984)].
Formoterol ist daher vorzüglich als dermatologisches Antiphlogistikum zur Behandlung von entzündlichen oder proliferativen, mit Entzündung verbundenen Dermatosen geeignet, insbesondere in Form der erfindungsgemässen topisch applizierbaren dermatologischen pharmazeutischen Präparate. Es kann bei verschiedenartigsten entzündlichen Dermatosen, insbesondere solchen akuter und subchronischer Art, sowohl allergischer als auch nicht-allergischer Natur, Verwendung finden. Weiterhin ist Formoterol zur Behandlung von proliferativen Hauterkrankungen, insbesondere solchen, die mit Entzündung verbunden sind, wie der Psoriasis, geeignet, und kann ebenso zur Behandlung von Hautirritationen, Exanthemen und Verbrennungen sowie zur Behandlung von Entzündungen der Augenbindehaut, der Lippen und der Genital- und Analregion Verwendung finden.Formoterol is therefore particularly suitable as a dermatological anti-inflammatory agent for the treatment of inflammatory or proliferative dermatoses associated with inflammation, in particular in the form of the topically applicable dermatological application according to the invention pharmaceutical preparations. It can be used in a wide variety of inflammatory dermatoses, in particular those of an acute and subchronic type, both allergic and non-allergic in nature. Formoterol is also suitable for the treatment of proliferative skin diseases, in particular those associated with inflammation, such as psoriasis, and can also be used for the treatment of skin irritations, rashes and burns as well as for the treatment of inflammation of the conjunctiva, the lips and the genital and Find anal region use.
Die vorliegende Erfindung betrifft ebenfalls ein Verfahren zur Behandlung entzündlicher Hauterkrankungen der vorbeschriebenen Art, gekennzeichnet durch die topische, d.h. dermale, Applikation einer Verbindung der Formel I oder eines ihrer pharmazeutisch verwendbaren Salze.The present invention also relates to a method for the treatment of inflammatory skin diseases of the type described above, characterized by the topical, i.e. dermal application of a compound of formula I or one of its pharmaceutically acceptable salts.
Die Erfindung betrifft gleichermassen die Verwendung einer Verbindung der Formel I oder eines ihrer pharmazeutisch verwendbaren Salze zur Behandlung von entzündlichen Hauterkrankungen unterschiedlichster Genese, insbesondere zur Behandlung von Dermatosen der vorstehend beschriebenen Art, sowie zur Herstellung der erfindungsgemässen dermatologischen pharmazeutischen Präparate.The invention also relates to the use of a compound of the formula I or one of its pharmaceutically usable salts for the treatment of inflammatory skin diseases of the most varied of origins, in particular for the treatment of dermatoses of the type described above, and for the production of the dermatological pharmaceutical preparations according to the invention.
Bei den erfindungsgemässen pharmazeutischen Präparaten, welche eine Verbindung der Formel I, insbesondere Formoterol, oder pharmazeutisch verwendbare Salze davon enthalten, handelt es sich um solche zur dermatologischen Anwendung an Warmblütern, wobei der pharmakologische Wirkstoff allein oder zusammen mit einem pharmazeutisch anwendbaren Trägermaterial enthalten ist. Die tägliche Dosierung des Wirkstoffs hängt von dem Alter und dem individuellen Zustand sowie von der Applikationsweise ab. Entsprechende Mittel mit einem Wirkstoffgehalt von etwa 0,00001 bis etwa 1 Gewichtsprozent, z.B. in Form von Crèmes, Salben oder Lösungen, können beispielsweise 2 bis 3 x täglich appliziert werden.The pharmaceutical preparations according to the invention which contain a compound of the formula I, in particular formoterol, or pharmaceutically acceptable salts thereof, are those for dermatological use on warm-blooded animals, the pharmacological active ingredient being contained alone or together with a pharmaceutically acceptable carrier material. The daily dosage of the active ingredient depends on the age and individual condition as well as on the mode of administration. Corresponding agents with an active ingredient content of about 0.00001 to about 1 percent by weight, for example in the form of creams, ointments or solutions, can be applied, for example, 2 to 3 times a day.
Als dermatologisch anwendbare pharmazeutische Präparate kommen in erster Linie Crèmes, Salben, Fettsalben, Pasten, Gele, Schäume, Tinkturen und Lösungen sowie zur Behandlung der Augenbindehaut Augentropfen in Frage, die jeweils beispielsweise von etwa 0,00001 bis etwa 1 Gewichtsprozent, insbesondere von etwa 0,0005 bis etwa 0,5 Gewichtsprozent, des Wirkstoffs enthalten.Suitable dermatologically applicable pharmaceutical preparations are primarily creams, ointments, fatty ointments, pastes, gels, foams, tinctures and solutions, and for treating the conjunctiva, eye drops, each of for example from about 0.00001 to about 1 percent by weight, in particular from about 0 , 0005 to about 0.5 percent by weight of the active ingredient.
Crèmes sind Oel-in-Wasser Emulsionen, die mehr als 50 % Wasser aufweisen. Als ölige Grundlage verwendet man in erster Linie Fettalkohole, z.B. Lauryl-, Cetyl- oder Stearylalkohol, Fettsäuren, z.B. Palmitin- oder Stearinsäure, flüssige bis feste Wachse, z.B. Isopropylmyristat, Wollwachs oder Bienenwachs, und/oder Kohlenwasserstoffe, z.B. Vaseline (Petrolatum) oder Paraffinöl. Als Emulgatoren kommen oberflächenaktive Substanzen mit vorwiegend hydrophilen Eigenschaften in Frage, wie entsprechende nichtionische Emulgatoren, z.B. Fettsäureester von Polyalkoholen oder Aethylenoxidaddukte davon, wie Polyglycerinfettsäureester oder Polyoxyäthylensorbitanfettsäureester (Tweens), ferner Polyoxyäthylenfettalkoholäther oder -fettsäureester, oder entsprechende, ionische Emulgatoren, wie Alkalimetallsalze von Fettalkoholsulfaten, z.B. Natriumlaurylsulfat, Natriumcetylsulfat oder Natriumstearylsulfat, die man üblicherweise in Gegenwart von Fettalkoholen, z.B. Cetylalkohol oder Stearylalkohol, verwendet. Zusätze zur Wasserphase sind u.a. Mittel, welche die Austrocknung der Crème vermindern, z.B. Polyalkohole, wie Glycerin, Sorbit, Propylenglykol und/oder Polyäthylenglykole, ferner Konservierungsmittel, Riechstoffe, etc.Creams are oil-in-water emulsions that contain more than 50% water. Fatty alcohols, e.g. Lauryl, cetyl or stearyl alcohol, fatty acids e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil. Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, e.g. Fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), furthermore polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are commonly used in the presence of fatty alcohols, e.g. Cetyl alcohol or stearyl alcohol. Additions to the water phase include Agents which reduce the drying out of the cream, e.g. Polyalcohols, such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
Salben sind Wasser-in-Oel-Emulsionen, die bis zu 70 %, vorzugsweise jedoch von etwa 20 % bis etwa 50 % Wasser oder wässrige Phasen enthalten. Als Fettphase kommen in erster Linie Kohlenwasserstoffe, z.B. Vaseline, Paraffinöl und/oder Hartparaffine in Frage, die zur Verbesserung des Wasserbindungsvermögens vorzugsweise geeignete Hydroxyverbindungen, wie Fettalkohole oder Ester davon, z.B. Cetylalkohol oder Wollwachsalkohole bzw. Wollwachs, enthalten. Emulgatoren sind entsprechende lipophile Substanzen, wie Sorbitanfettsäureester (Spans), z.B. Sorbitanoleat und/oder Sorbitaniso stearat. Zusätze zur Wasserphase sind u.a. Feuchthaltungsmittel, wie Polyalkohole, z.B. Glycerin, Propylenglykol, Sorbit und/oder Polyäthylenglykol, sowie Konservierungsmittel, Riechstoffe, etc.Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases. The fatty phase primarily includes hydrocarbons, for example petroleum jelly, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols or wool wax, in order to improve their water binding capacity. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), for example sorbitan oleate and / or sorbitan iso stearate. Additives to the water phase include humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and / or polyethylene glycol, and also preservatives, fragrances, etc.
Fettsalben sind wasserfrei und enthalten als Grundlage insbesondere Kohlenwasserstoffe, z.B. Paraffin, Vaseline und/oder flüssige Paraffine, ferner natürliche oder partialsynthetische Fette, z.B. Kokosfettsäuretriglycerid, oder vorzugsweise gehärtete Oele, z.B. hydriertes Erdnuss- oder Rizinusöl, ferner Fettsäurepartialester des Glycerins, z.B. Glycerinmono- und -distearat, sowie z.B. die im Zusammenhang mit den Salben erwähnten, die Wasseraufnahmefähigkeit steigernden Fettalkohole, Emulgatoren und/oder Zusätze.Fatty ointments are anhydrous and contain hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fats, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate, as well as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments which increase the water absorption capacity.
Pasten sind Crèmes und Salben mit sekretabsorbierenden Puderbestandteilen, wie Metalloxiden, z.B. Titanoxid oder Zinkoxid, ferner Talk und/oder Aluminiumsilikate, welche die Aufgabe haben, vorhandene Feuchtigkeit oder Sekrete zu binden.Pastes are creams and ointments with secretion-absorbing powder components such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
Bei den Gelen wird zwischen wässrigen und wasserfreien oder wasserarmen Gelen unterschieden, die aus quellbaren, gelbildenden Materialien bestehen. In erster Linie kommen transparente Hydrogele auf der Grundlage anorganischer oder organischer Makromoleküle zum Einsatz. Hochmolekulare anorganische Komponenten mit gelbildenden Eigenschaften sind überwiegend wasserhaltige Silikate, wie Aluminiumsilikate, z.B. Betonit, Magnesium-Aluminium-Silikate, z.B. Veegum, oder kolloidale Kieselsäure, z.B. Aerosil. Als hochmolekulare organische Stoffe werden beispielsweise natürliche, halbsynthetische oder synthetische Makromoleküle verwendet. Natürliche und halbsynthetische Polymere leiten sich beispielsweise von Polysacchariden mit den unterschiedlichsten Kohlenhydratbausteinen ab, wie Cellulosen, Stärken, Tragant, arabisches Gummi, Agar-Agar, Gelatine, Alginsäure und deren Salze, z.B. Natriumalginat, und deren Derivate, wie Niederalkylcellulosen, z.B. Methyl- oder Aethylcellulosen, Carboxy- oder Hydroxyniederalkylcellulose, z.B. Carboxymethyl- oder Hydroxyäthylcellulosen. Die Bausteine synthetischer, gelbildender Makromoleküle sind beispielsweise entsprechend substituierte ungesättigte Aliphaten, wie Vinylalkohol, Vinylpyrrolidin, Acryl- oder Methacrylsäure. Als Beispiele für solche Polymere sind Polyvinylalkohol-Derivate, wie Polyviol, Polyvinylpyrrolidine, wie Kollidon, Polyacrylate bzw. Polymethacrylate, wie Rohagit S oder Eudispert, zu nennen. Den Gelen können übliche Zusatzmittel, wie Konservierungs- oder Riechstoffe, zugegeben werden.A distinction is made between aqueous and water-free or low-water gels, which consist of swellable, gel-forming materials. Transparent hydrogels based on inorganic or organic macromolecules are primarily used. High-molecular inorganic components with gel-forming properties are predominantly water-containing silicates, such as aluminum silicates, for example concrete, magnesium-aluminum silicates, for example Veegum, or colloidal silica, for example Aerosil. Natural, semisynthetic or synthetic macromolecules, for example, are used as high-molecular organic substances. Natural and semi-synthetic polymers are derived, for example, from polysaccharides with a wide variety of carbohydrate components, such as celluloses, starches, tragacanth, arabic gum, agar-agar, gelatin, alginic acid and their salts, for example sodium alginate, and their derivatives, such as lower alkyl celluloses, for example methyl or Ethyl celluloses, carboxy or hydroxy lower alkyl cellulose, for example carboxymethyl or hydroxyethyl celluloses. The building blocks of synthetic, gel-forming macromolecules are, for example appropriately substituted unsaturated aliphatics such as vinyl alcohol, vinyl pyrrolidine, acrylic or methacrylic acid. Examples of such polymers are polyvinyl alcohol derivatives, such as polyviol, polyvinylpyrrolidines, such as Kollidon, polyacrylates or polymethacrylates, such as Rohagit S or Eudispert. Common additives, such as preservatives or fragrances, can be added to the gels.
Schäume werden z.B. aus Druckbehältern verabreicht und sind in Aerosolform vorliegende flüssige Oel-in-Wasser-Emulsionen, wobei halogenierte Kohlenwasserstoffe, wie Chlorfluorniederalkane, z.B. Dichlordifluormethan und Dichlortetrafluoräthan, als Treibmittel verwendet werden. Als Oelphase verwendet man u.a. Kohlenwasserstoffe, z.B. Paraffinöl, Fettalkohole, z.B. Cetylalkohol, Fettsäureester, z.B. Isopropylmyristat, und/oder andere Wachse. Als Emulgatoren verwendet man u.a. Gemische von solchen mit vorwiegend hydrophilen Eigenschaften, wie Polyoxyäthylen-sorbitan-fettsäureester (Tweens), und solchen mit vorwiegend lipophilen Eigenschaften, wie Sorbitanfettsäureester (Spans). Dazu kommen die üblichen Zusätze, wie Konservierungsmittel, etc.Foams are e.g. administered from pressure vessels and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro lower alkanes e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents. The oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohols, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes. The emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual additives such as preservatives, etc.
Tinkturen und Lösungen weisen meistens eine wässrig-äthanolische Grundlage auf, der u.a. Polyalkohole, z.B. Glycerin, Glykole und/oder Polyäthylenglykol, als Feuchthaltemittel zur Herabsetzung der Verdunstung, und rückfettende Substanzen, wie Fettsäureester mit niedrigen Polyäthylenglykolen, d.h. im wässrigen Gemisch lösliche, lipophile Substanzen als Ersatz für die der Haut mit dem Aethanol entzogenen Fettsubstanzen, und, falls notwendig, andere Hilfs- und Zusatzmittel beigegeben sind.Tinctures and solutions mostly have a watery-ethanol base, which among other things Polyalcohols, e.g. Glycerin, glycols and / or polyethylene glycol, as humectants to reduce evaporation, and refatting substances such as fatty acid esters with low polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture as a substitute for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives are added.
Augentropfen sind zumeist sterile wässrige Lösungen, die auf den physiologischen pH-Bereich von 6 bis 8 eingestellt sind. Die Konzentration der zur pH-Einstellung beispielsweise verwendeten Puffer, wie Phosphat- oder Acetatpuffer, ist so gewählt, dass der pH-Wert der Tränenflüssigkeit nicht langfristig beeinflusst und dadurch eine Schmerzempfindung ausgelöst wird. Die Isotonie mit der Tränenflüssigkeit wird meist durch Zugabe von Salzen, wie Natriumcitrat oder vorzugsweise Natriumchlorid, oder Mannit erreicht. Zusätzlich werden die üblichen Hilfsstoffe, beispielsweise Antioxidantien, wie Natriumpyrosulfit, Konservierungsmittel, wie Benzalkoniumchlorid, Cetylpyridiniumchlorid oder 2-Phenyl-äthylalkohol, sowie gegebenenfalls Lösungsvermittler, z.B. Polyoxyäthylensorbitanmonooleat, Polyoxyäthylenglykol oder α- bzw. β-Cyclodextrin, zugesetzt.Eye drops are mostly sterile aqueous solutions that are adjusted to the physiological pH range from 6 to 8. The concentration of the buffers used for pH adjustment, such as phosphate or acetate buffers, is selected so that the pH of the tear fluid is not influenced over the long term and a pain sensation is triggered. The isotony with the Lacrimal fluid is usually achieved by adding salts, such as sodium citrate or preferably sodium chloride, or mannitol. In addition, the usual auxiliaries, for example antioxidants such as sodium pyrosulfite, preservatives such as benzalkonium chloride, cetylpyridinium chloride or 2-phenylethyl alcohol, and optionally solubilizers, for example polyoxyethylene sorbitan monooleate, polyoxyethylene glycol or α- or β-cyclodextrin, are added.
Die Herstellung der dermatologisch anwendbaren pharmazeutischen Präparate erfolgt in an sich bekannter Weise durch Vermischung mit dafür üblichen pharmazeutischen Hilfsstoffen, z.B. durch Lösen oder Suspendieren des Wirkstoffs in der Grundlage oder in einem Teil davon, falls notwendig. Zur Herstellung von Emulsionen, in denen der Wirkstoff in einer der flüssigen Phasen gelöst ist, wird der Wirkstoff in der Regel vor der Emulgierung in dieser gelöst; zur Herstellung von Suspensionen, in denen der Wirkstoff in der Emulsion suspendiert ist, wird der Wirkstoff nach der Emulgierung mit einem Teil der Grundlage vermischt und dann dem Rest der Formulierung beigegeben.The dermatologically applicable pharmaceutical preparations are produced in a manner known per se by mixing with conventional pharmaceutical auxiliaries, e.g. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary. To prepare emulsions in which the active ingredient is dissolved in one of the liquid phases, the active ingredient is usually dissolved in the latter before the emulsification; to produce suspensions in which the active ingredient is suspended in the emulsion, the active ingredient is mixed with part of the base after the emulsification and then added to the rest of the formulation.
Die nachfolgenden Beispiele illustrieren die oben beschriebene Erfindung, sie sollen jedoch diese in ihrem Umfang in keiner Weise einschränken. Temperaturen sind in Celsiusgraden angegeben.The following examples illustrate the invention described above, but are not intended to limit the scope thereof in any way. Temperatures are given in degrees Celsius.
Beispiel 1: Eine Salbe, enthaltend 0,05 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino]-äthyl]-formanilid oder sein Semifumarat, kann wie folgt hergestellt werden:
Zusammensetzung:
Wirkstoff 0,05 %
Vaseline 45,00 %
Paraffinöl 19,60 %
Cetylalkohol 5,00 %
Bienenwachs 5,00 %
Sorbitan-sesquioleat 5,00 %
p-Hydroxybenzoesäureester 0,20 %
Wasser, entmineralisiert, bis zu 100,00 % Example 1: An ointment containing 0.05% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] -formanilide or its semifumarate, can be prepared as follows:
Composition:
Active substance 0.05%
Vaseline 45.00%
Paraffin oil 19.60%
Cetyl alcohol 5.00%
Beeswax 5.00%
Sorbitan sesquioleate 5.00%
p-hydroxybenzoic acid ester 0.20%
Water, demineralized, up to 100.00%
Die Fettstoffe und Emulgatoren werden zusammengeschmolzen. Das Konservierungsmittel wird in Wasser gelöst, und die Lösung in die Fettschmelze bei erhöhter Temperatur einemulgiert. Nach dem Erkalten wird eine Suspension des Wirkstoffs in einem Teil der Fettschmelze in die Emulsion eingearbeitet.The fatty substances and emulsifiers are melted together. The preservative is dissolved in water and the solution is emulsified into the fat melt at elevated temperature. After cooling, a suspension of the active ingredient is incorporated into part of the fat melt in the emulsion.
Beispiel 2: Eine Crème, enthaltend 0,5 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino]-äthyl]-formanilid oder sein Semifumarat, kann wie folgt hergestellt werden:
Zusammensetzung:
Wirkstoff 0,5 %
Isopropylpalmitat 8,0 %
Cetylpalmitat 1,5 %
Siliconöl 100 0,5 %
Sorbitanmonostearat 3,0 %
Polysorbat 60 3,5 %
1,2-Propylenglykol PH 20,0 %
Acrylsäurepolymerisat 0,5 %
Triäthanolamin 0,7 %
Wasser, entmineralisiert, bis zu 100,0 % Example 2: A cream containing 0.5% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] -formanilide or its semifumarate, can be prepared as follows:
Composition:
Active ingredient 0.5%
Isopropyl palmitate 8.0%
Cetyl palmitate 1.5%
Silicone oil 100 0.5%
Sorbitan monostearate 3.0%
Polysorbate 60 3.5%
1,2-propylene glycol PH 20.0%
Acrylic acid polymer 0.5%
Triethanolamine 0.7%
Water, demineralized, up to 100.0%
Das Acrylsäurepolymerisat wird in einem Gemisch aus entmineralisiertem Wasser und 1,2-Propylenglykol suspendiert. Unter Rühren wird hierauf Triäthanolamin zugegeben, wodurch ein Schleim erhalten wird. Ein Gemisch aus Isopropylpalmitat, Cetylpalmitat, Siliconöl, Sorbitanmonostearat und Polysorbat wird auf ca. 75° erwärmt und unter Rühren in den gleichfalls auf ca. 75° erwärmten Schleim eingearbeitet. Die auf Raumtemperatur abgekühlte Crème-Grundlage wird hierauf zur Herstellung eines Konzentrates mit dem Wirkstoff verwendet. Das Konzentrat wird mittels eines Durchlaufhomogenisators homogenisiert und dann portionsweise der Grundlage hinzugefügt.The acrylic acid polymer is suspended in a mixture of demineralized water and 1,2-propylene glycol. Triethanolamine is then added with stirring, giving a mucus. A mixture of isopropyl palmitate, cetyl palmitate, silicone oil, Sorbitan monostearate and polysorbate are heated to about 75 ° and incorporated into the mucus, which has also been heated to about 75 °, with stirring. The cream base cooled to room temperature is then used to produce a concentrate with the active ingredient. The concentrate is homogenized by means of a continuous homogenizer and then added to the base in portions.
Beispiel 3: Eine Crème, enthaltend 0,05 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino-äthyl]-formanilid oder sein Semifumarat, kann wie folgt erhalten werden:
Zusammensetzung:
Wirkstoff 0,05 %
Cetylpalmitat PH 2,00 %
Cetylalkohol PH 2,00 %
Triglyceridgemisch gesättigter mittelfettiger Fettsäuren 5,00 %
Stearinsäure 3,00 %
Glycerinstearat PH 4,00 %
Cetomacrogol 1000 1,00 %
mikrokristalline Cellulose 0,50 %
1,2-Propylenglykol, dest. 20,00 %
Wasser, entmineralisiert, bis zu 100,00 % Example 3: A cream containing 0.05% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino -ethyl] -formanilide or its semifumarate can be obtained as follows:
Composition:
Active substance 0.05%
Cetyl palmitate PH 2.00%
Cetyl alcohol PH 2.00%
Triglyceride mixture of saturated medium fatty acids 5.00%
Stearic acid 3.00%
Glycerol stearate pH 4.00%
Cetomacrogol 1000 1.00%
microcrystalline cellulose 0.50%
1,2-propylene glycol, dist. 20.00%
Water, demineralized, up to 100.00%
Cetylalkohol, Cetylpalmitat, das Triglyceridgemisch, Stearinsäure und Glycerinstearat werden zusammengeschmolzen. Die mikrokristalline Cellulose wird in einem Teil des Wassers dispergiert. Im restlichen Teil des Wassers wird Cetomacrogol gelöst und das Propylenglykol sowie der Schleim dazu gemischt. Die Fettphase wird anschliessend unter Rühren zur Wasserphase gegeben und kaltgerührt. Schliesslich wird der Wirkstoff mit einem Teil der Grundlage angerieben und hierauf die Anreibung in den Rest der Crème eingearbeitet.Cetyl alcohol, cetyl palmitate, the triglyceride mixture, stearic acid and glycerol stearate are melted together. The microcrystalline cellulose is dispersed in part of the water. Cetomacrogol is dissolved in the remaining part of the water and the propylene glycol and the mucus are mixed with it. The fat phase is then added to the water phase with stirring and stirred cold. Finally, the active ingredient is rubbed with part of the base and the rubbing is then incorporated into the rest of the cream.
Beispiel 4: Ein transparentes Hydrogel, enthaltend 0,5 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]amino]-äthyl]-formanilid oder sein Semifumarat, wird wie folgt hergestellt:
Zusammensetzung:
Wirkstoff 0,5 %
Propylenglykol 10,0 - 20,0 %
Isopropanol 20,0 %
Hydroxypropyl-methylcellulose 2,0 %
Wasser ad 100,0 % Example 4: A transparent hydrogel containing 0.5% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] -formanilide or its semi-fumarate is made as follows:
Composition:
Active ingredient 0.5%
Propylene glycol 10.0 - 20.0%
Isopropanol 20.0%
Hydroxypropyl methyl cellulose 2.0%
Water ad 100.0%
Die Hydroxypropyl-methylcellulose wird im Wasser gequollen. Der Wirkstoff wird in einem Gemisch aus Isopropanol und Propylenglykol gelöst. Anschliessend wird die Wirkstofflösung mit einem gequollenen Cellulose-Derivat vermischt und, wenn erwünscht, mit Riechstoffen (0,1 %) versetzt.The hydroxypropyl methyl cellulose is swollen in the water. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with a swollen cellulose derivative and, if desired, fragrances (0.1%) are added.
Beispiel 5: Ein transparentes Hydrogel, enthaltend 0,005 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino]-äthyl]-formanilid oder sein Semifumarat, wird wie folgt hergestellt:
Zusammensetzung:
Wirkstoff 0,005 %
Propylenglykol 20,0 %
Isopropanol 20,0 %
Acrylsäurepolymerisat 2,0 %
Triäthanolamin 3,0 %
Wasser ad 100,0 % Example 5: A transparent hydrogel containing 0.005% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino] -ethyl] -formanilide or its semi-fumarate is made as follows:
Composition:
Active ingredient 0.005%
Propylene glycol 20.0%
Isopropanol 20.0%
Acrylic acid polymer 2.0%
Triethanolamine 3.0%
Water ad 100.0%
Acrylsäurepolymerisat und Wasser werden dispergiert und mit Triäthanolamin neutralisiert. Der Wirkstoff wird in einem Gemisch aus Isopropanol und Propylenglykol gelöst. Anschliessend wird die Wirkstofflösung mit dem Gel vermischt, wobei, wenn erwünscht, Riechstoff (0,1 %) zugegeben werden kann.Acrylic acid polymer and water are dispersed and neutralized with triethanolamine. The active ingredient is dissolved in a mixture of isopropanol and propylene glycol. The active ingredient solution is then mixed with the gel, it being possible, if desired, to add fragrance (0.1%).
Beispiel 6: Ein Schaumspray, enthaltend 0,01 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino]-äthyl]- formanilid oder sein Semifumarat, kann folgendermassen hergestellt werden:
Zusammensetzung:
Wirkstoff 0,01 %
Cetylalkohol PH 1,70 %
Paraffinöl, dickflüssig 1,00 %
Isopropylmyristat 2,00 %
Cetomacrogol 1000 2,40 %
Sorbitanmonostearat 1,50 %
1,2-Propylenglykol PH 5,00 %
Methylparaben 0,18 %
Propylparaben 0,02 %
Chemoderm 314 0,10 %
Wasser, entmineralisiert, bis zu 100,00 % Example 6: A foam spray containing 0.01% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino ] -ethyl] - formanilide or its semifumarate, can be prepared as follows:
Composition:
Active ingredient 0.01%
Cetyl alcohol PH 1.70%
Paraffin oil, viscous 1.00%
Isopropyl myristate 2.00%
Cetomacrogol 1000 2.40%
Sorbitan monostearate 1.50%
1,2-propylene glycol pH 5.00%
Methyl paraben 0.18%
Propylparaben 0.02%
Chemoderm 314 0.10%
Water, demineralized, up to 100.00%
Cetylalkohol, Paraffinöl, Isopropylmyristat, Cetomacrogol und Sorbitanstearat werden zusammengeschmolzen. Methyl- und Propylparaben werden in heissem Wasser gelöst. Die Schmelze und die Lösung werden anschliessend vermischt. Der Wirkstoff, in Propylenglykol suspendiert, wird in die Grundlage eingearbeitet. Anschliessend wird Chemoderm zugeführt und mit Wasser auf das Endgewicht ergänzt.Cetyl alcohol, paraffin oil, isopropyl myristate, cetomacrogol and sorbitan stearate are melted together. Methyl and propyl paraben are dissolved in hot water. The melt and the solution are then mixed. The active ingredient, suspended in propylene glycol, is incorporated into the base. Chemoderm is then added and water is added to the final weight.
20 ml des Gemisches werden in eine Aluminiumblockdose eingefüllt. Die Dose wird mit einem Ventil versehen, und das Treibgas wird unter Druck eingefüllt.20 ml of the mixture are poured into an aluminum block can. The can is fitted with a valve and the propellant is filled under pressure.
Beispiel 7: Augentropfen, enthaltend 0,3 % 2-Hydroxy-5-[(RS)-1-hydroxy-2-[[(RS)-1-(p-methoxyphenyl)-prop-2-yl]-amino]-äthyl]-formanilid oder sein Semifumarat, können z.B. folgendermassen hergestellt werden:
Zusammensetzung (für 10 000 Flaschen mit je 10 ml Augentropfenlösung):
Wirkstoff 0,30 %
Dinatriumphosphat 0,31 %
Zitronensäure 0,15 %
Natriumchlorid 0,35 %
Natriumpyrosulfit 0,10 %
Benzalkoniumchlorid 0,01 %
Wasser, entmineralisiert, bis zu 100,00 % Example 7: Eye drops containing 0.3% 2-hydroxy-5 - [(RS) -1-hydroxy-2 - [[(RS) -1- (p-methoxyphenyl) prop-2-yl] amino] -ethyl] -formanilide or its semi-fumarate, can be prepared for example as follows:
Composition (for 10,000 bottles with 10 ml eye drop solution):
Active ingredient 0.30%
Disodium phosphate 0.31%
Citric acid 0.15%
Sodium chloride 0.35%
Sodium pyrosulfite 0.10%
Benzalkonium chloride 0.01%
Water, demineralized, up to 100.00%
Der Wirkstoff und alle angegebenen Zusatzsstoffe werden unter einer Stickstoffatmosphäre in 80 l entmineralisertes Wasser eingerührt. Nach der vollständigen Auflösung aller Bestandteile wird die Lösung mit entmineralisertem Wasser auf 100 l aufgefüllt, in einem Autoklaven bei 120° während 20 Minuten sterilisiert und anschliessend unter sterilen Bedingungen durch ein Membranfilter (Porendurchmesser: 0,2 µm) filtriert. Je 10 ml des Filtrats werden unter aseptischen Bedingungen in eine Flasche mit Tropfpipettenverschluss abgefüllt.The active ingredient and all of the additives mentioned are stirred into 80 l of demineralized water under a nitrogen atmosphere. After all components have completely dissolved, the solution is made up to 100 l with demineralized water, sterilized in an autoclave at 120 ° for 20 minutes and then filtered under sterile conditions through a membrane filter (pore diameter: 0.2 μm). Each 10 ml of the filtrate is filled into a bottle with a dropper cap under aseptic conditions.
Beispiel 8: In analoger Weise wie in den Beispielen 1 bis 7 beschrieben kann man auch dermatologisch anwendbare pharmazeutische Präparate, die ein anderes pharmazeutisch verwendbares Salz von Formoterol enthalten, herstellen. Example 8: In a manner analogous to that described in Examples 1 to 7, it is also possible to prepare dermatologically applicable pharmaceutical preparations which contain another pharmaceutically acceptable salt of formoterol.
Beispiel 9: In analoger Weise wie in den Beispielen 1 bis 7 beschrieben kann man auch dermatologisch anwendbare pharmazeutische Präparate, die eine andere Verbindung der Formel I oder ein pharmazeutisch verwendbares Salz davon enthalten, herstellen. Example 9: Dermatologically applicable pharmaceutical preparations which contain another compound of the formula I or a pharmaceutically acceptable salt thereof can also be prepared in a manner analogous to that described in Examples 1 to 7.
Claims (10)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH2290/86 | 1986-06-05 | ||
CH229086 | 1986-06-05 |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0252286A2 true EP0252286A2 (en) | 1988-01-13 |
EP0252286A3 EP0252286A3 (en) | 1990-01-17 |
EP0252286B1 EP0252286B1 (en) | 1992-07-08 |
Family
ID=4230316
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP87107958A Expired - Lifetime EP0252286B1 (en) | 1986-06-05 | 1987-06-02 | Pharmaceutical preparations for topical use, process for their manufacture and their use |
Country Status (10)
Country | Link |
---|---|
US (1) | US4975466A (en) |
EP (1) | EP0252286B1 (en) |
JP (1) | JPS6322015A (en) |
KR (1) | KR880000091A (en) |
AU (1) | AU614712B2 (en) |
CA (1) | CA1305423C (en) |
DE (1) | DE3780226D1 (en) |
DK (1) | DK167841B1 (en) |
IE (1) | IE59612B1 (en) |
PH (1) | PH25150A (en) |
Cited By (2)
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EP0416925A2 (en) * | 1989-09-07 | 1991-03-13 | Glaxo Group Limited | Use of 4-hydroxy-alpha 1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol or its salts in the treatment of allergy and inflammation |
EP0872246A1 (en) * | 1995-11-30 | 1998-10-21 | Kissei Pharmaceutical Co., Ltd. | Novel drug for relieving pain and promoting the removal of calculi in urolithiasis |
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US5434304A (en) * | 1990-09-26 | 1995-07-18 | Aktiebolaget Astra | Process for preparing formoterol and related compounds |
US6866839B2 (en) * | 1991-04-05 | 2005-03-15 | Sepracor Inc. | Methods and compositions for treating pulmonary disorders using optically pure (R,R)-formoterol |
US6299863B1 (en) | 1992-04-03 | 2001-10-09 | Sepracor Inc. | Aerosol formulations containing micronized optically pure (R,R) formoterol for bronchodilating therapy |
US5795564A (en) * | 1991-04-05 | 1998-08-18 | Sepracor, Inc. | Methods and compositions for treating pulmonary disorders using optically pure (R,R)-formoterol |
US5135954A (en) * | 1991-05-24 | 1992-08-04 | The Regents Of The University Of California | Use of formoterol for treatment of tissue injury |
EP0943330A4 (en) * | 1996-10-04 | 2001-08-16 | Saitama Daiichi Seiyaku Kabush | Patch |
US6319464B1 (en) * | 1996-12-13 | 2001-11-20 | Alcon Manufacturing, Ltd. | Use of low molecular weight amino alcohols in ophthalmic compositions |
US6303145B2 (en) | 1999-05-10 | 2001-10-16 | Sepracor Inc. | (S,R) formoterol methods and compositions |
US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
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US8900554B2 (en) | 2002-10-25 | 2014-12-02 | Foamix Pharmaceuticals Ltd. | Foamable composition and uses thereof |
US7575739B2 (en) | 2003-04-28 | 2009-08-18 | Foamix Ltd. | Foamable iodine composition |
US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
JP5108234B2 (en) * | 2005-02-07 | 2012-12-26 | 日本特殊陶業株式会社 | Micro heater and sensor |
MX2007012794A (en) | 2005-04-13 | 2008-02-22 | Astion Pharma As | Beta-2 adrenoceptor agonists for treating connective tissue diseases of the skin. |
US9023863B2 (en) * | 2006-07-14 | 2015-05-05 | Stiefel Research Australia Pty Ltd | Fatty acid pharmaceutical foam |
US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
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US8735422B2 (en) * | 2009-02-06 | 2014-05-27 | Skinvisible Pharmaceuticals, Inc. | Cationic pharmaceutically active ingredient containing composition, and methods for manufacturing and using |
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CA2769677A1 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
CA2769625C (en) | 2009-07-29 | 2017-04-11 | Foamix Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
AU2010302350B2 (en) | 2009-10-02 | 2015-06-18 | Journey Medical Corporation | Surfactant-free water-free foamable compositions, breakable foams and gels and their uses |
US8174881B2 (en) | 2009-11-24 | 2012-05-08 | Micron Technology, Inc. | Techniques for reducing disturbance in a semiconductor device |
US10398641B2 (en) | 2016-09-08 | 2019-09-03 | Foamix Pharmaceuticals Ltd. | Compositions and methods for treating rosacea and acne |
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US3994974A (en) * | 1972-02-05 | 1976-11-30 | Yamanouchi Pharmaceutical Co., Ltd. | α-Aminomethylbenzyl alcohol derivatives |
DE2305092A1 (en) * | 1972-02-05 | 1973-08-16 | Yamanouchi Pharma Co Ltd | Alpha-aminomethylbenzyl alcohol derivs. - prepd. by redn. of corresponding protected derivs. |
DE2401450A1 (en) * | 1973-01-16 | 1974-07-18 | John James Voorhees | PHARMACEUTICAL COMPOSITION FOR THE RELIEF OF SKIN PROLIFERATIONAL DISEASES |
GB1531718A (en) * | 1974-11-20 | 1978-11-08 | Pharmacia As | Phenylethanolamines |
DK31578A (en) * | 1977-02-03 | 1978-08-04 | Allen & Hanburys Ltd | PROCEDURE FOR THE PRODUCTION OF BENZENE DERIVATIVES |
JPS5592312A (en) * | 1978-12-29 | 1980-07-12 | Yamanouchi Pharmaceut Co Ltd | Suppository containing bronchodilating compound |
US4303637A (en) * | 1980-04-04 | 1981-12-01 | Alza Corporation | Medication indicated for ocular hypertension |
JPS56140915A (en) * | 1980-04-07 | 1981-11-04 | Yamanouchi Pharmaceut Co Ltd | Pharmaceutical preparation for solid drug |
JPS60174716A (en) * | 1984-02-21 | 1985-09-09 | Yamanouchi Pharmaceut Co Ltd | Medicinal patch |
-
1987
- 1987-05-29 PH PH35328A patent/PH25150A/en unknown
- 1987-06-02 DE DE8787107958T patent/DE3780226D1/en not_active Expired - Lifetime
- 1987-06-02 EP EP87107958A patent/EP0252286B1/en not_active Expired - Lifetime
- 1987-06-03 KR KR870005609A patent/KR880000091A/en not_active Application Discontinuation
- 1987-06-03 CA CA000538656A patent/CA1305423C/en not_active Expired - Lifetime
- 1987-06-04 AU AU73836/87A patent/AU614712B2/en not_active Ceased
- 1987-06-04 JP JP62139076A patent/JPS6322015A/en active Granted
- 1987-06-04 DK DK289487A patent/DK167841B1/en not_active IP Right Cessation
- 1987-06-04 IE IE148587A patent/IE59612B1/en not_active IP Right Cessation
-
1988
- 1988-12-07 US US07/282,928 patent/US4975466A/en not_active Expired - Fee Related
Non-Patent Citations (1)
Title |
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Agents and Actions, Vol. 19, No. 5/6, 18.-20. Juni 1986, Seiten 368-370, Birkhaeuser Verlag, Basel, CH; W. PIGNAT et al.: "How specific is the arachidonic acid-induced mouse ear oedema for lipoxygenase (LO)- and cyclooxygenase (CO)- inhibitors?", Tabelle 1. * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0416925A2 (en) * | 1989-09-07 | 1991-03-13 | Glaxo Group Limited | Use of 4-hydroxy-alpha 1-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol or its salts in the treatment of allergy and inflammation |
EP0416925A3 (en) * | 1989-09-07 | 1991-09-25 | Glaxo Group Limited | Use of 4-hydroxy-alpha 1-(((6-(4-phenylbutoxy)hexyl)amino)methyl)-1,3-benzenedimethanol or its salts in the treatment of allergy and inflammation |
EP0872246A1 (en) * | 1995-11-30 | 1998-10-21 | Kissei Pharmaceutical Co., Ltd. | Novel drug for relieving pain and promoting the removal of calculi in urolithiasis |
EP0872246B1 (en) * | 1995-11-30 | 2003-02-19 | Kissei Pharmaceutical Co., Ltd. | Drug for relieving pain and promoting the removal of calculi in urolithiasis |
Also Published As
Publication number | Publication date |
---|---|
IE59612B1 (en) | 1994-03-09 |
KR880000091A (en) | 1988-03-23 |
EP0252286A3 (en) | 1990-01-17 |
AU7383687A (en) | 1987-12-10 |
AU614712B2 (en) | 1991-09-12 |
JPH0448774B2 (en) | 1992-08-07 |
EP0252286B1 (en) | 1992-07-08 |
DK289487A (en) | 1987-12-06 |
CA1305423C (en) | 1992-07-21 |
PH25150A (en) | 1991-03-13 |
DE3780226D1 (en) | 1992-08-13 |
US4975466A (en) | 1990-12-04 |
DK289487D0 (en) | 1987-06-04 |
DK167841B1 (en) | 1993-12-27 |
IE871485L (en) | 1987-12-05 |
JPS6322015A (en) | 1988-01-29 |
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